RESUMO
Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicin-induced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631-42. ©2016 AACR.
Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Inflamação/induzido quimicamente , Receptor 4 Toll-Like/metabolismo , Animais , Endotoxinas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Regulação para CimaRESUMO
Colorectal cancer (CRC) is one of the most common cancers leading to high mortality. However, long-term administration of anti-tumor therapy for CRC is not feasible due to the side effects. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), particularly DHA and EPA, exert protection against CRC, but the mechanisms are unclear. Here, we show that ω-3 PUFAs inhibit proliferation and induce apoptosis of CRC cells in vitro and alleviate AOM/DSS-induced mice colorectal cancer in vivo. Moreover, ω-3 PUFAs promote phosphorylation and cytoplasmic retention of YAP and this effect was mediated by MST1/2 and LATS1, suggesting that the canonical Hippo Pathway is involved in ω-3 PUFAs function. We further confirmed that increase of pYAP by ω-3 PUFAs was mediated by GPRs, including GPR40 and GPR120, which subsequently activate PKA via Gαs, thus inducing the Hippo pathway activation. These data provide a novel DHA/EPA-GPR40/120-Gαs-PKA-MST1/2-LATS1-YAP signaling pathway which is linked to ω-3 PUFAs-induced inhibition of cell proliferation and promotion of apoptosis in CRC cells, indicating a mechanism that could explain the anti-cancer action of ω-3 PUFAs.
Assuntos
Neoplasias Colorretais/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Azoximetano/química , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/terapia , Citoplasma/metabolismo , Sulfato de Dextrana/química , Células HT29 , Via de Sinalização Hippo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fosfoproteínas/metabolismo , Fosforilação , Transporte Proteico , Proteínas de Sinalização YAPRESUMO
The difficulty of controlling drug release at an intracellular level remains a key challenge for maximising drug safety and efficacy. We demonstrate herein a new, efficient and convenient approach to extracellularly control the intracellular release of doxorubicin (DOX), by designing a delivery system that harnesses the interactions between the system and a particular set of cellular machinery. By simply adding a small-molecule chemical into the cell medium, we could lower the release rate of DOX in the cytosol, and thereby increase its accumulation in the nuclei while decreasing its presence at mitochondria. Delivery of DOX with this system effectively prevented DOX-induced mitochondria damage that is the main mechanism of its toxicity, while exerting the maximum efficacy of this anti-cancer chemotherapeutic agent. The present study sheds light on the design of drug delivery systems for extracellular control of intracellular drug delivery, with immediate therapeutic implications.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismoRESUMO
Hypoxic regions are common in solid tumors and have an impact on tumor progression and on the therapeutic response. However, the underlying mechanism for hypoxic tumor microenvironment has not been entirely elucidated. Recently, long noncoding RNAs (lncRNAs) are being increasingly recognized to contribute to carcinogenesis through diverse mechanisms. To date, several lncRNAs have been described in hypoxia-associated cancer process, implying a potential role in maintaining cellular homeostasis and enabling an adaptive survival under hypoxic stress conditions. While it has been widely accepted that a complex cellular network of gene products, such as protein and miRNA, take part in hypoxic cancer progression, it remains largely elusive how lncRNAs participate in it. In this review, we introduce an update view of lncRNAs, focusing on hypoxia-related lncRNAs. We hereby summarize the cause and consequence of hypoxia-modulated lncRNAs in cancer as well as their functional mechanisms, highlighting the specific roles of lncRNAs in hypoxia response in cancer.
Assuntos
Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Animais , Hipóxia Celular , Humanos , Neoplasias/genética , RNA Longo não Codificante/genética , RNA Neoplásico/genéticaRESUMO
The Hippo pathway was originally identified and named through screening for mutations in Drosophila, and the core components of the Hippo pathway are highly conserved in mammals. In the Hippo pathway, MST1/2 and LATS1/2 regulate downstream transcription coactivators YAP and TAZ, which mainly interact with TEAD family transcription factors to promote tissue proliferation, self-renewal of normal and cancer stem cells, migration, and carcinogenesis. The Hippo pathway was initially thought to be quite straightforward; however, recent studies have revealed that YAP/TAZ is an integral part and a nexus of a network composed of multiple signaling pathways. Therefore, in this review, we will summarize the latest findings on events upstream and downstream of YAP/TAZ and the ways of regulation of YAP/TAZ. In addition, we also focus on the crosstalk between the Hippo pathway and other tumor-related pathways and discuss their potential as therapeutic targets.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Regulação da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Hipóxia/metabolismo , Sistema de Sinalização das MAP Quinases , Ácido Mevalônico/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Neoplasias/genética , Fosfatidilinositol 3-Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores Androgênicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fatores de Transcrição/genética , Via de Sinalização WntRESUMO
Epidemiological and preclinical data have demonstrated the preventative effects of ω-3 polyunsaturated fatty acids, including docosahexaenoic acid (DHA), on prostate cancer. However, there are inconsistencies in these previous studies and the underlying mechanisms remain to be elucidated. In the present study, the androgen receptor (AR), which is a transcription factor involved in cell proliferation and prostate carcinogenesis, was identified as a target of DHA. It was revealed that DHA inhibited hormonedependent growth of LNCaP prostate cancer cells. Reverse transcription-quantitative polymerase chain reaction analysis revealed that treatment with DHA caused no alteration in the transcribed mRNA expression levels of the AR gene. However, immunoblotting revealed that this treatment reduces the protein expression level of the AR. The androgeninduced genes were subsequently repressed by treatment with DHA. It was demonstrated that DHA exhibits no effect on the translation process of the AR, however, it promotes the proteasomemediated degradation of the AR. Therefore, the present study provided a novel mechanism by which DHA exhibits an inhibitory effect on growth of prostate cancer cells.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Proteólise/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Androgênios/genética , Androgênios/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/genéticaRESUMO
Tumour-associated macrophages (TAMs) are a set of macrophages residing in the tumour microenvironment. They play essential roles in mediating tumour angiogenesis, metastasis and immune evasion. Delivery of therapeutic agents to eliminate TAMs can be a promising strategy for cancer immunotherapy but an efficient vehicle to target these cells is still in pressing need. In this study, we developed a bisphosphonate-glucomannan conjugate that could efficiently target and specifically eliminate TAMs in the tumour microenvironment. We employed the polysaccharide from Bletilla striata (BSP), a glucomannan affinitive for macrophages that express abundant mannose receptors, to conjugate alendronate (ALN), a bisphosphonate compound with in vitro macrophage-inhibiting activities. In both in vitro and in vivo tests, the prepared ALN-BSP conjugate could preferentially accumulate in macrophages and induced them into apoptosis. In the subcutaneous S180 tumour-bearing mice model, the treatment using ALN-BSP effectively eliminated TAMs, remarkably inhibited angiogenesis, recovered local immune surveillance, and eventually suppressed tumour progression, without eliciting any unwanted effect such as systematic immune response. Interestingly, ALN alone failed to exhibit any anti-TAM activity in vivo, probably because this compound was susceptible to the mildly acidic tumour microenvironment. Taken together, these results demonstrate the potential of ALN-BSP as a safe and efficient tool targeted at direct depletion of TAMs for cancer immunotherapy.